PROJECT SUMMARY/ABSTRACT This proposal seeks to address a gap in knowledge about the clinical and biological factors that are associated with resilience to the development of smoking-related lung disease and protective pathways that may be leveraged to develop new therapies and preventative approaches for COPD. Tobacco smoke is the most common environmental risk factor for COPD, however despite this strong association, it is estimated that only 15-25% of smokers will develop COPD when using spirometric criteria for the diagnosis. It is uncertain why some smokers are spirometrically ?resilient? to the damaging pulmonary effects of cigarette smoke. One premise is that the traditional spirometric definition of COPD may underestimate disease and overestimate the percentage of smokers who are truly ?resilient?. Specifically, a significant proportion of smokers who do not meet spirometric criteria for COPD still have respiratory symptoms, exacerbations, and radiographic abnormalities, which suggests they are experiencing adverse effects from tobacco smoke exposure and indicate they may not be truly ?resilient.? One factor underlying resilience may be protective factors in the airway epithelium since this is the first anatomic surface of the lung exposed to the highest concentration of tobacco smoke. My long-term goal is to identify pathobiological mechanisms related to resilience as opposed to disease onset and progression. My central hypotheses are that 1)?resilience? is better defined using multiple clinical domains and that 2)variability in the airway epithelial response to chronic smoke exposure, as measured by gene expression alterations, can modify disease susceptibility, and provide insight into the mechanisms of ?resilience.? I propose to test these hypotheses in two specific aims. Aim 1: Systematically develop a new multidimensional definition of a ?resilient smoker? using multiple clinical domains and determine its prevalence and biological significance in a longitudinal study of COPD. Aim 2: Identify airway epithelial gene expression markers associated with the ?resilient smoker? using SPIROMICS, an NHLBI-funded multi-site longitudinal cohort study of COPD which has obtained detailed clinical, radiographic, physiological data, and bronchoscopic samples of airway epithelial cells. The public health impact of these aims is that successful completion will identify new strategies to treat and prevent COPD. This overall approach is innovative because most translational studies focus on pathways associated with disease rather than protection from development of the disease. This proposal is directly responsive to NHLBI priorities because it focuses on Objective 1 the NHLBI Strategic Vision: ?Understand normal biological function and resilience?. Furthermore, this award will have a positive impact on Dr. Anita Oh's training, as a clinical fellow at the University of California San Francisco, by providing her with the support necessary to acquire knowledge and refine her statistical and genomic skills to foster her research career and progress towards becoming an independent researcher.